Systems-level Approach Research Articles

Recent Advances in the Systems Biology of Aging.

Reductionist studies have contributed greatly to our understanding of the basic biology of aging in recent years but we still do not understand fundamental mechanisms for many identified drugs and pathways. Use of systems approaches will help us move forward in our understanding of aging. Recent Advances: Recent work described here has illustrated the power of systems biology to inform our understanding of aging through the study of (i) diet restriction, (ii) neurodegenerative disease, and (iii) biomarkers of aging. Although we do not understand all of the individual genes and pathways that affect aging, as we continue to uncover more of them, we have now also begun to synthesize existing data using systems-level approaches, often to great effect. The three examples noted here all benefit from computational approaches that were unknown a few years ago, and from biological insights gleaned from multiple model systems, from aging laboratories as well as many other areas of biology. Many new technologies, such as single-cell sequencing, advances in epigenetics beyond the methylome (specifically, assay for transposase-accessible chromatin with high throughput sequencing ), and multiomic network studies, will increase the reach of systems biologists. This suggests that approaches similar to those described here will continue to lead to striking findings, and to interventions that may allow us to delay some of the many age-associated diseases in humans; perhaps sooner that we expect. Antioxid. Redox Signal. 29, 973-984.

A systems-level approach for investigating organophosphorus pesticide toxicity

The full understanding of the single and joint toxicity of a variety of organophosphorus (OP) pesticides is still unavailable, because of the extreme complex mechanism of action. This study established a systems-level approach based on systems toxicology to investigate OP pesticide toxicity by incorporating ADME/T properties, protein prediction, and network and pathway analysis. The results showed that most OP pesticides are highly toxic according to the ADME/T parameters, and can interact with significant receptor proteins to cooperatively lead to various diseases by the established OP pesticide -protein and protein-disease networks. Furthermore, the studies that multiple OP pesticides potentially act on the same receptor proteins and/or the functionally diverse proteins explained that multiple OP pesticides could mutually enhance toxicological synergy or additive on a molecular/systematic level. To the end, the integrated pathways revealed the mechanism of toxicity of the interaction of OP pesticides and elucidated the pathogenesis induced by OP pesticides. This study demonstrates a systems-level approach for investigating OP pesticide toxicity that can be further applied to risk assessments of various toxins, which is of significant interest to food security and environmental protection.

When the drugs don't work: treatment-resistant schizophrenia, serotonin and serendipity.

Treatment-resistant schizophrenia is a serious clinical problem. We adopt a systems-level approach positing a greater role for cognitive control mechanisms in the development of psychotic symptoms and illustrate the clinical application of this via a case report of treatment-resistant patients treated successfully with adjunct pro-cognitive serotonergic medication.

A systems level approach to temporal expression dynamics in Drosophila reveals clusters of long term memory genes.

The ability to integrate experiential information and recall it in the form of memory is observed in a wide range of taxa, and is a hallmark of highly derived nervous systems. Storage of past experiences is critical for adaptive behaviors that anticipate both adverse and positive environmental factors. The process of memory formation and consolidation involve many synchronized biological events including gene transcription, protein modification, and intracellular trafficking: However, many of these molecular mechanisms remain illusive. With Drosophila as a model system we use a nonassociative memory paradigm and a systems level approach to uncover novel transcriptional patterns. RNA sequencing of Drosophila heads during and after memory formation identified a number of novel memory genes. Tracking the dynamic expression of these genes over time revealed complex gene networks involved in long term memory. In particular, this study focuses on two functional gene clusters of signal peptides and proteases. Bioinformatics network analysis and prediction in combination with high-throughput RNA sequencing identified previously unknown memory genes, which when genetically knocked down resulted in behaviorally validated memory defects.

To fail is human: remediating remediation in medical education.

IntroductionRemediating failing medical learners has traditionally been a craft activity responding to individual learner and remediator circumstances. Although there have been moves towards more systematic approaches to remediation (at least at the institutional level), these changes have tended to focus on due process and defensibility rather than on educational principles. As remediation practice evolves, there is a growing need for common theoretical and systems-based perspectives to guide this work.MethodsThis paper steps back from the practicalities of remediation practice to take a critical systems perspective on remediation in contemporary medical education. In doing so, the authors acknowledge the complex interactions between institutional, professional, and societal forces that are both facilitators of and barriers to effective remediation practices.ResultsThe authors propose a model that situates remediation within the contexts of society as a whole, the medical profession, and medical education institutions. They also outline a number of recommendations to constructively align remediation principles and practices, support a continuum of remediation practices, destigmatize remediation, and develop institutional communities of practice in remediation.DiscussionMedical educators must embrace a responsible and accountable systems-level approach to remediation if they are to meet their obligations to provide a safe and effective physician workforce.

Network analysis reveals a causal role of mitochondrial gene activity in atherosclerotic lesion formation

Background and aimsMitochondrial damage and augmented production of reactive oxygen species (ROS) may represent an intermediate step by which hypercholesterolemia exacerbates atherosclerotic lesion formation. MethodsTo test this hypothesis, in mice with severe but genetically reversible hypercholesterolemia (i.e. the so called Reversa mouse model), we performed time-resolved analyses of mitochondrial transcriptome in the aortic arch employing a systems-level network approach. ResultsDuring hypercholesterolemia, we observed a massive down-regulation (>28%) of mitochondrial genes, specifically at the time of rapid atherosclerotic lesion expansion and foam cell formation, i.e. between 30 and 40 weeks of age. Both phenomena - down-regulation of mitochondrial genes and lesion expansion - were largely reversible by genetically lowering plasma cholesterol (by >80%, from 427 to 54 ± 31 mg/L) at 30 weeks. Co-expression network analysis revealed that both mitochondrial signature genes were highly connected in two modules, negatively correlating with lesion size and supported as causal for coronary artery disease (CAD) in humans, as expression-associated single nucleotide polymorphisms (eSNPs) representing their genes overlapped markedly with established disease risk loci. Within these modules, we identified the transcription factor estrogen related receptor (ERR)-α and its co-factors PGC1-α and -β, i.e. two members of the peroxisome proliferator-activated receptor γ co-activator 1 family of transcription regulators, as key regulatory genes. Together, these factors are known as major orchestrators of mitochondrial biogenesis and antioxidant responses. ConclusionsUsing a network approach, we demonstrate how hypercholesterolemia could hamper mitochondrial activity during atherosclerosis progression and pinpoint potential therapeutic targets to counteract these processes.

Pharmacometabolomics Informs Quantitative Radiomics for Glioblastoma Diagnostic Innovation.

Applications of omics systems biology technologies have enormous promise for radiology and diagnostics in surgical fields. In this context, the emerging fields of radiomics (a systems scale approach to radiology using a host of technologies, including omics) and pharmacometabolomics (use of metabolomics for patient and disease stratification and guiding precision medicine) offer much synergy for diagnostic innovation in surgery, particularly in neurosurgery. This synthesis of omics fields and applications is timely because diagnostic accuracy in central nervous system tumors still challenges decision-making. Considering the vast heterogeneity in brain tumors, disease phenotypes, and interindividual variability in surgical and chemotherapy outcomes, we believe that diagnostic accuracy can be markedly improved by quantitative radiomics coupled to pharmacometabolomics and related health information technologies while optimizing economic costs of traditional diagnostics. In this expert review, we present an innovation analysis on a systems-level multi-omics approach toward diagnostic accuracy in central nervous system tumors. For this, we suggest that glioblastomas serve as a useful application paradigm. We performed a literature search on PubMed for articles published in English between 2006 and 2016. We used the search terms "radiomics," "glioblastoma," "biomarkers," "pharmacogenomics," "pharmacometabolomics," "pharmacometabonomics/pharmacometabolomics," "collaborative informatics," and "precision medicine." A list of the top 4 insights we derived from this literature analysis is presented in this study. For example, we found that (i) tumor grading needs to be better refined, (ii) diagnostic precision should be improved, (iii) standardization in radiomics is lacking, and (iv) quantitative radiomics needs to prove clinical implementation. We conclude with an interdisciplinary call to the metabolomics, pharmacy/pharmacology, radiology, and surgery communities that pharmacometabolomics coupled to information technologies (chemoinformatics tools, databases, collaborative systems) can inform quantitative radiomics, thus translating Big Data and information growth to knowledge growth, rational drug development and diagnostics innovation for glioblastomas, and possibly in other brain tumors.

Personalized vaccinology: A review

At the current time, the field of vaccinology remains empirical in many respects. Vaccine development, vaccine immunogenicity, and vaccine efficacy have, for the most part, historically been driven by an empiric “isolate-inactivate-inject” paradigm. In turn, a population-level public health paradigm of “the same dose for everyone for every disease” model has been the normative thinking in regard to prevention of vaccine-preventable infectious diseases. In addition, up until recently, no vaccines had been designed specifically to overcome the immunosenescence of aging, consistent with a post-WWII mentality of developing vaccines and vaccine programs for children. It is now recognized that the current lack of knowledge concerning how immune responses to vaccines are generated is a critical barrier to understanding poor vaccine responses in the elderly and in immunoimmaturity, discovery of new correlates of vaccine immunogenicity (vaccine response biomarkers), and a directed approach to new vaccine development.The new fields of vaccinomics and adversomics provide models that permit global profiling of the innate, humoral, and cellular immune responses integrated at a systems biology level. This has advanced the science beyond that of reductionist scientific approaches by revealing novel interactions between and within the immune system and other biological systems (beyond transcriptional level), which are critical to developing “downstream” adaptive humoral and cellular responses to infectious pathogens and vaccines. Others have applied systems level approaches to the study of antibody responses (a.k.a. “systems serology”), [1] high-dimensional cell subset immunophenotyping through CyTOF, [2,3] and vaccine induced metabolic changes [4]. In turn, this knowledge is being utilized to better understand the following: identifying who is at risk for which infections; the level of risk that exists regarding poor immunogenicity and/or serious adverse events; and the type or dose of vaccine needed to fully protect an individual. In toto, such approaches allow for a personalized approach to the practice of vaccinology, analogous to the substantial inroads that individualized medicine is playing in other fields of human health and medicine. Herein we briefly review the field of vaccinomics, adversomics, and personalized vaccinology.

Analysis of air gap volume in structural firefighter turnout suit constructions in relation to heat loss

Air layers in multi-layer firefighter clothing ensembles resist heat transfer from the body to the environment. By reducing the volume of air between clothing layers, heat loss may be improved throughout the multi-layer firefighter turnout suit clothing system, potentially leading to reduced heat strain for the wearer. This research utilized a systems-level approach to the methodology in order to measure the effects of fabric properties and garment air gap dimensions on clothing system heat loss through specially configured turnout suit constructions. One experimental configuration incorporated a tight fitting stretchable moisture barrier garment. Another construction used thermal knit underwear to represent a closer fitting thermal liner. Air gap surface area, volume, and thickness were estimated using three-dimensional body scanning. This study showed the significant impact of fabric air permeability and clothing air gap volume on heat loss through structural firefighter suits. Tested individually, the tighter fitting moisture barrier construction permitted greater heat loss in comparison to the traditional fit moisture barrier. Heat loss differences associated with moisture barrier fit were not observed when the moisture barriers were configured in the three-layer turnout clothing system. This research showed that microclimate air gap volume is strongly correlated with total heat loss. It confirmed the significant impact of clothing air layers on heat loss through firefighter turnout systems.

Closing the attainment gap – a realistic proposition or an elusive pipe-dream?

The attainment gap associated with socio-economic status is an international problem that is highly resistant to change. This conceptual paper critiques the drive by the Scottish Government to address the attainment gap through the Scottish Attainment Challenge and the National Improvement Framework. It draws upon a range of theoretical perspectives but principally examines the problem through the lens of Steiner-Khamsi’s concepts of ‘reception’ and ‘translation’ of policy and through examination of the international and national (Scottish) policy contexts. The paper argues that, rather than focussing narrowly upon attainment outcomes, an holistic approach should be adopted which takes account of the economic, social and relational constraints which impact upon families in poverty, calling for a systems-level approach. ‘Schools cannot go it alone’: there is a need to focus upon a wide range of public policy to redress inequalities in society. Whilst the Scottish Government has looked to the London/City/National Challenge as a potential solution to the problem, the complexities and limitations of policy borrowing need to be understood. Higher Education Institutions, government agencies, local authorities and schools need to work in partnership to develop research informed practice which will impact upon learning outcomes for all children and young people.

A Systems Approach to Perception and Action

ABSTRACTOn the 50th anniversary of its publication, we look back on some of the intellectual contributions of Gibson's (1966) The Senses Considered as Perceptual Systems. This work is often seen as contributing a new perspective to our understanding of the 5 senses. In this paper, we explore another intellectual contribution: Gibson's treatment of perception–action as an irreducible, functional system. We review select examples of systems thinking from the physical, animal, and human social domains. Our suggestion is that a systems-level approach to social interactions would have been a natural extension of Gibson's ideas.

Fluid and flexible minds: Intelligence reflects synchrony in the brain's intrinsic network architecture.

Human intelligence has been conceptualized as a complex system of dissociable cognitive processes, yet studies investigating the neural basis of intelligence have typically emphasized the contributions of discrete brain regions or, more recently, of specific networks of functionally connected regions. Here we take a broader, systems perspective in order to investigate whether intelligence is an emergent property of synchrony within the brain’s intrinsic network architecture. Using a large sample of resting-state fMRI and cognitive data (n = 830), we report that the synchrony of functional interactions within and across distributed brain networks reliably predicts fluid and flexible intellectual functioning. By adopting a whole-brain, systems-level approach, we were able to reliably predict individual differences in human intelligence by characterizing features of the brain’s intrinsic network architecture. These findings hold promise for the eventual development of neural markers to predict changes in intellectual function that are associated with neurodevelopment, normal aging, and brain disease.

Systematic, multiparametric analysis of Mycobacterium tuberculosis intracellular infection offers insight into coordinated virulence.

A key to the pathogenic success of Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the capacity to survive within host macrophages. Although several factors required for this survival have been identified, a comprehensive knowledge of such factors and how they work together to manipulate the host environment to benefit bacterial survival are not well understood. To systematically identify Mtb factors required for intracellular growth, we screened an arrayed, non-redundant Mtb transposon mutant library by high-content imaging to characterize the mutant-macrophage interaction. Based on a combination of imaging features, we identified mutants impaired for intracellular survival. We then characterized the phenotype of infection with each mutant by profiling the induced macrophage cytokine response. Taking a systems-level approach to understanding the biology of identified mutants, we performed a multiparametric analysis combining pathogen and host phenotypes to predict functional relationships between mutants based on clustering. Strikingly, mutants defective in two well-known virulence factors, the ESX-1 protein secretion system and the virulence lipid phthiocerol dimycocerosate (PDIM), clustered together. Building upon the shared phenotype of loss of the macrophage type I interferon (IFN) response to infection, we found that PDIM production and export are required for coordinated secretion of ESX-1-substrates, for phagosomal permeabilization, and for downstream induction of the type I IFN response. Multiparametric clustering also identified two novel genes that are required for PDIM production and induction of the type I IFN response. Thus, multiparametric analysis combining host and pathogen infection phenotypes can be used to identify novel functional relationships between genes that play a role in infection.

A thermal management system using ammonium carbamate as an endothermic heat sink

The issue of managing low-quality waste heat onboard modern high-performance aircraft represents a critical performance limitation that can severely restrict flight envelopes, preclude the integration of high-power electronics, or compromise system reliability. The principal engineering challenges to the thermal systems engineer are the large quantities of heat involved, low (and carefully controlled) coolant temperatures required, and the limited availability of heat sinks to which the waste heat must ultimately be rejected. The use of endothermic chemical reactions to serve as controllable, flight envelope-independent heat sinks has considerable potential in addressing the latter of these engineering challenges, but must be integrated as part of a systems-level approach in order to address all three - acquisition, control, and rejection. In this paper, we introduce and demonstrate a thermal management system (TMS) architecture integrating a vapor compression heat pump, phase change thermal energy storage, and heat exchanger-reactor (HEX reactor) to utilize the endothermic decomposition of ammonium carbamate as an expendable heat sink. An experimental proof-of-concept study was conducted to demonstrate acquisition of both static and time- variant thermal loads, coolant temperature regulation typical of electronics cooling applications, and rejection of the thermal load to an expendable heat sink. The proposed TMS successfully managed pulsed and steady thermal loads while maintaining a coolant temperature within 1°C of the target set point. During steady-state operation, the TMS was able to achieve coefficients of performance (COP) in the neighborhood of 3 with nearly 100% efficiency in expendable heat sink utilization; when subjected to dynamic heat loads, the use of a thermal energy storage material allowed simple control schemes to be used to maintain TMS stability.

Binary hypothesis-based impact damage detection for composite material system embedded with fiber Bragg gratings

In recent years, the use of composite materials has helped achieve ever-increasing performance requirements in marine, aerospace, and civil structures. A parallel interest in the structural health monitoring of composites has developed to further improve performance by reducing overall life-cycle costs. In this work, a network of embedded fiber Bragg gratings is employed as part of a damage detection system for an impact damage scenario in a composite laminate material system. Delamination damage is incrementally introduced into the laminate via repeated impacts with a drop weight pendulum system. Using vibration time histories between impacts from a simulated, pseudorandom operational loading, and damage-sensitive features were extracted and placed within a Mahalanobis distance-based discrimination framework. The statistical modeling for hypothesis testing is also presented to give a full, systems-level approach to a damage detection system from data acquisition to ultimate decision making.

Detecting Perturbed Subpathways towards Mouse Lung Regeneration Following H1N1 Influenza Infection

It has already been established by the systems-level approaches that the future of predictive disease biomarkers will not be sketched by plain lists of genes or proteins or other biological entities but rather integrated entities that consider all underlying component relationships. Towards this orientation, early pathway-based approaches coupled expression data with whole pathway interaction topologies but it was the recent approaches that zoomed into subpathways (local areas of the entire biological pathway) that provided more targeted and context-specific candidate disease biomarkers. Here, we explore the application potential of PerSubs, a graph-based algorithm which identifies differentially activated disease-specific subpathways. PerSubs is applicable both for microarray and RNA-Seq data and utilizes the Kyoto Encyclopedia of Genes and Genomes (KEGG) database as reference for biological pathways. PerSubs operates in two stages: first, identifies differentially expressed genes (or uses any list of disease-related genes) and in second stage, treating each gene of the list as start point, it scans the pathway topology around to build meaningful subpathway topologies. Here, we apply PerSubs to investigate which pathways are perturbed towards mouse lung regeneration following H1N1 influenza infection.

Graph theoretical approaches towards understanding differences in frontoparietal and default mode networks in Autism.

Autism Spectrum Disorder is a complex developmental disorder affecting 1 in 68 children in the United States. While the prevalence may be on the rise, we currently lack a firm understanding of the etiology of the disease, and diagnosis is made purely on behavioral observation and informant report. As one method to improve our understanding of the disease, the current study took a systems-level approach by assessing the causal interactions among the frontoparietal and default mode networks using structural covariance of a large Autism dataset. Although preliminary, we report diffuse yet subtle changes throughout these networks when comparing age and sex matched controls to ASD patients.

Neighbours of cancer-related proteins have key influence on pathogenesis and could increase the drug target space for anticancer therapies

Even targeted chemotherapies against solid cancers show a moderate success increasing the need to novel targeting strategies. To address this problem, we designed a systems-level approach investigating the neighbourhood of mutated or differentially expressed cancer-related proteins in four major solid cancers (colon, breast, liver and lung). Using signalling and protein–protein interaction network resources integrated with mutational and expression datasets, we analysed the properties of the direct and indirect interactors (first and second neighbours) of cancer-related proteins, not found previously related to the given cancer type. We found that first neighbours have at least as high degree, betweenness centrality and clustering coefficient as cancer-related proteins themselves, indicating a previously unknown central network position. We identified a complementary strategy for mutated and differentially expressed proteins, where the affect of differentially expressed proteins having smaller network centrality is compensated with high centrality first neighbours. These first neighbours can be considered as key, so far hidden, components in cancer rewiring, with similar importance as mutated proteins. These observations strikingly suggest targeting first neighbours as a novel strategy for disrupting cancer-specific networks. Remarkably, our survey revealed 223 marketed drugs already targeting first neighbour proteins but applied mostly outside oncology, providing a potential list for drug repurposing against solid cancers. For the very central first neighbours, whose direct targeting would cause several side effects, we suggest a cancer-mimicking strategy by targeting their interactors (second neighbours of cancer-related proteins, having a central protein affecting position, similarly to the cancer-related proteins). Hence, we propose to include first neighbours to network medicine based approaches for (but not limited to) anticancer therapies.

Review—Electrochemical Growth of Carbon Nanotubes and Graphene from Ambient Carbon Dioxide: Synergy with Conventional Gas-Phase Growth Mechanisms

The rising levels of atmospheric CO2 threaten the promise of human sustainability on earth. Electrochemical conversion of CO2 into secondary chemicals and materials presents the most economically viable approach to solve this global challenge, and provides a method to utilize otherwise wasted CO2 as a chemical feedstock for the production of valuable products. Challenged by the processing cost versus value of converted materials, known routes for the production of hydrocarbons and alcohol products remain impractical. Electrochemical CO2 conversion into high-value carbon nanostructures presents a new area of research with the opportunity to build upon the last two decades of understanding of gas-phase synthesis processes for fullerenes, carbon nanotubes, and graphene. However, efforts so far to convert atmospheric carbon dioxide into functional carbon materials are limited by a systems-level approach that provides only coarse control over the types and quality of materials that can be synthesized. In this short review, we make a strong case for the synergy between the catalytic mechanisms that have been developed over past decades to understand carbon nanostructure growth and the emerging research area where electrochemical reduction of ambient CO2 can be used to produce carbon nanostructured materials. This presents a new opportunity for researchers to address one of the most pressing environmental issues for modern mankind with the synthesis of carbon materials that will shape our future.

A systems-level approach reveals new gene regulatory modules in the developing ear.

The inner ear is a complex vertebrate sense organ, yet it arises from a simple epithelium, the otic placode. Specification towards otic fate requires diverse signals and transcriptional inputs that act sequentially and/or in parallel. Using the chick embryo, we uncover novel genes in the gene regulatory network underlying otic commitment and reveal dynamic changes in gene expression. Functional analysis of selected transcription factors reveals the genetic hierarchy underlying the transition from progenitor to committed precursor, integrating known and novel molecular players. Our results not only characterize the otic transcriptome in unprecedented detail, but also identify new gene interactions responsible for inner ear development and for the segregation of the otic lineage from epibranchial progenitors. By recapitulating the embryonic programme, the genes and genetic sub-circuits discovered here might be useful for reprogramming naïve cells towards otic identity to restore hearing loss.